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Estrogen-related receptor gamma is a key regulator of muscle mitochondrial activity and oxidative capacity.

Rangwala SM, Wang X, Calvo JA, Lindsley L, Zhang Y, Deyneko G, Beaulieu V, Gao J, Turner G, Markovits J - J. Biol. Chem. (2010)

Bottom Line: Furthermore, peak oxidative capacity was higher in the transgenics as compared with control littermates.Our data indicate that ERRgamma plays an important role in causing a shift toward slow twitch muscle type and, concomitantly, a greater capacity for endurance exercise.Thus, the activation of this nuclear receptor provides a potential node for therapeutic intervention for diseases such as obesity, which is associated with reduced oxidative metabolism and a lower type I fiber content in skeletal muscle.

View Article: PubMed Central - PubMed

Affiliation: Cardiovascular and Metabolism Disease Area, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA. shamina.rangwala@novartis.com

ABSTRACT
Estrogen-related receptor gamma (ERRgamma) regulates the perinatal switch to oxidative metabolism in the myocardium. We wanted to understand the significance of induction of ERRgamma expression in skeletal muscle by exercise. Muscle-specific VP16ERRgamma transgenic mice demonstrated an increase in exercise capacity, mitochondrial enzyme activity, and enlarged mitochondria despite lower muscle weights. Furthermore, peak oxidative capacity was higher in the transgenics as compared with control littermates. In contrast, mice lacking one copy of ERRgamma exhibited decreased exercise capacity and muscle mitochondrial function. Interestingly, we observed that increased ERRgamma in muscle generates a gene expression profile that closely overlays that of red oxidative fiber-type muscle. We further demonstrated that a small molecule agonist of ERRbeta/gamma can increase mitochondrial function in mouse myotubes. Our data indicate that ERRgamma plays an important role in causing a shift toward slow twitch muscle type and, concomitantly, a greater capacity for endurance exercise. Thus, the activation of this nuclear receptor provides a potential node for therapeutic intervention for diseases such as obesity, which is associated with reduced oxidative metabolism and a lower type I fiber content in skeletal muscle.

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Schematic model displaying the central role for ERRγ in the transcriptional network regulating muscle fiber type and function.
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Figure 7: Schematic model displaying the central role for ERRγ in the transcriptional network regulating muscle fiber type and function.

Mentions: Because the phenotype of the transgenic ERRγ mice is strongly reminiscent of mouse models for peroxisome proliferator-activated receptor δ (30) or the MEF2/histone deacetylase/calcineurin pathway (29, 47), an important question that arises is whether these transcriptional factors have redundant roles in muscle. There are salient differences among these genetic models that point to a specific role for each protein in the control of muscle structure, function, and metabolism. Unlike the peroxisome proliferator-activated receptor δ transgenic models, we did not observe a resistance of our animals to a high fat diet, nor did they demonstrate an improvement in glucose tolerance.3 The MEF2 pathway controls expression of the slow muscle fiber genes but does not impact the mitochondrial or metabolic gene program. Our gene expression studies indicate that ERRγ plays a broader role in the control of biological processes such as angiogenesis and calcium handling in skeletal muscle. Thus, future studies will aim at comparing the gene expression patterns in these models directly to be able to tease apart the specific roles of these pathways in skeletal muscle. The schematic in Fig. 7 illustrates the complex transcriptional network regulating aspects of muscle gene expression.


Estrogen-related receptor gamma is a key regulator of muscle mitochondrial activity and oxidative capacity.

Rangwala SM, Wang X, Calvo JA, Lindsley L, Zhang Y, Deyneko G, Beaulieu V, Gao J, Turner G, Markovits J - J. Biol. Chem. (2010)

Schematic model displaying the central role for ERRγ in the transcriptional network regulating muscle fiber type and function.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2903389&req=5

Figure 7: Schematic model displaying the central role for ERRγ in the transcriptional network regulating muscle fiber type and function.
Mentions: Because the phenotype of the transgenic ERRγ mice is strongly reminiscent of mouse models for peroxisome proliferator-activated receptor δ (30) or the MEF2/histone deacetylase/calcineurin pathway (29, 47), an important question that arises is whether these transcriptional factors have redundant roles in muscle. There are salient differences among these genetic models that point to a specific role for each protein in the control of muscle structure, function, and metabolism. Unlike the peroxisome proliferator-activated receptor δ transgenic models, we did not observe a resistance of our animals to a high fat diet, nor did they demonstrate an improvement in glucose tolerance.3 The MEF2 pathway controls expression of the slow muscle fiber genes but does not impact the mitochondrial or metabolic gene program. Our gene expression studies indicate that ERRγ plays a broader role in the control of biological processes such as angiogenesis and calcium handling in skeletal muscle. Thus, future studies will aim at comparing the gene expression patterns in these models directly to be able to tease apart the specific roles of these pathways in skeletal muscle. The schematic in Fig. 7 illustrates the complex transcriptional network regulating aspects of muscle gene expression.

Bottom Line: Furthermore, peak oxidative capacity was higher in the transgenics as compared with control littermates.Our data indicate that ERRgamma plays an important role in causing a shift toward slow twitch muscle type and, concomitantly, a greater capacity for endurance exercise.Thus, the activation of this nuclear receptor provides a potential node for therapeutic intervention for diseases such as obesity, which is associated with reduced oxidative metabolism and a lower type I fiber content in skeletal muscle.

View Article: PubMed Central - PubMed

Affiliation: Cardiovascular and Metabolism Disease Area, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA. shamina.rangwala@novartis.com

ABSTRACT
Estrogen-related receptor gamma (ERRgamma) regulates the perinatal switch to oxidative metabolism in the myocardium. We wanted to understand the significance of induction of ERRgamma expression in skeletal muscle by exercise. Muscle-specific VP16ERRgamma transgenic mice demonstrated an increase in exercise capacity, mitochondrial enzyme activity, and enlarged mitochondria despite lower muscle weights. Furthermore, peak oxidative capacity was higher in the transgenics as compared with control littermates. In contrast, mice lacking one copy of ERRgamma exhibited decreased exercise capacity and muscle mitochondrial function. Interestingly, we observed that increased ERRgamma in muscle generates a gene expression profile that closely overlays that of red oxidative fiber-type muscle. We further demonstrated that a small molecule agonist of ERRbeta/gamma can increase mitochondrial function in mouse myotubes. Our data indicate that ERRgamma plays an important role in causing a shift toward slow twitch muscle type and, concomitantly, a greater capacity for endurance exercise. Thus, the activation of this nuclear receptor provides a potential node for therapeutic intervention for diseases such as obesity, which is associated with reduced oxidative metabolism and a lower type I fiber content in skeletal muscle.

Show MeSH
Related in: MedlinePlus